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Blood and tissue TMB help predict checkpoint inhibition response in NSCLC
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
REPORTING FROM ASCO 2018
Key clinical point: High bTMB and tTMB may help predict checkpoint inhibition response in NSCLC patients.
Major finding: PFS in NSCLC patients in the B-F1RST study was 9.5 vs. 2.8 months in those with a high vs. low bTMB score (hazard ratio, 0.49).
Study details: The phase 2b B-F1RST study including 58 evaluable patients and a retrospective analysis of 7 studies including 987 evaluable patients.
Disclosures: Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
Sources: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
Hemophilia adherence tied to perception of disease
More than half (56%) of adult patients with hemophilia are adherent to a prescribed prophylaxis regimen, but compliance appears less likely among patients who are having difficulty coping with pain or have a high conviction of disease.
Ana Torres-Ortuño, PhD, of the University of Murcia (Spain) and her colleagues performed a multicenter, cross-sectional descriptive study of 23 adult patients with severe hemophilia A or hemophilia B using various validated questionnaires that measured quality of life, disease perception, coping strategies, and treatment adherence.
The researchers found that Patients who experienced haemarthrosis with greater frequency had significantly greater adherence in terms of dosing (P less than .05), planning (P less than .05), and skipping (P less than .01). Similarly, patients with HIV infection were more adherent in terms of frequency of infusion than patients without infection.
The researchers also found significant correlations among all the psychosocial variables measured and adherence to prophylaxis. For instance, patients who had poorer quality of life related to managing their physical health, pain, and emotions showed poorer planning of their treatment. Patients who had difficulty remembering treatment had poorer quality of life related to pain and vitality, but they also had greater conviction of disease and hypochondriasis.
“Intervention programmes should be aimed more at changing barriers that patients and caregivers encounter when accepting diagnosis and how they can adapt their resources and skills to better take advantage of the progress made in treatments,” the researchers wrote.
The study was supported by a grant from Pfizer. The researchers reported having no financial disclosures.
SOURCE: Torres-Ortuño A et al. Vox Sang. 2018 May 24. doi: 10.1111/vox.12669.
More than half (56%) of adult patients with hemophilia are adherent to a prescribed prophylaxis regimen, but compliance appears less likely among patients who are having difficulty coping with pain or have a high conviction of disease.
Ana Torres-Ortuño, PhD, of the University of Murcia (Spain) and her colleagues performed a multicenter, cross-sectional descriptive study of 23 adult patients with severe hemophilia A or hemophilia B using various validated questionnaires that measured quality of life, disease perception, coping strategies, and treatment adherence.
The researchers found that Patients who experienced haemarthrosis with greater frequency had significantly greater adherence in terms of dosing (P less than .05), planning (P less than .05), and skipping (P less than .01). Similarly, patients with HIV infection were more adherent in terms of frequency of infusion than patients without infection.
The researchers also found significant correlations among all the psychosocial variables measured and adherence to prophylaxis. For instance, patients who had poorer quality of life related to managing their physical health, pain, and emotions showed poorer planning of their treatment. Patients who had difficulty remembering treatment had poorer quality of life related to pain and vitality, but they also had greater conviction of disease and hypochondriasis.
“Intervention programmes should be aimed more at changing barriers that patients and caregivers encounter when accepting diagnosis and how they can adapt their resources and skills to better take advantage of the progress made in treatments,” the researchers wrote.
The study was supported by a grant from Pfizer. The researchers reported having no financial disclosures.
SOURCE: Torres-Ortuño A et al. Vox Sang. 2018 May 24. doi: 10.1111/vox.12669.
More than half (56%) of adult patients with hemophilia are adherent to a prescribed prophylaxis regimen, but compliance appears less likely among patients who are having difficulty coping with pain or have a high conviction of disease.
Ana Torres-Ortuño, PhD, of the University of Murcia (Spain) and her colleagues performed a multicenter, cross-sectional descriptive study of 23 adult patients with severe hemophilia A or hemophilia B using various validated questionnaires that measured quality of life, disease perception, coping strategies, and treatment adherence.
The researchers found that Patients who experienced haemarthrosis with greater frequency had significantly greater adherence in terms of dosing (P less than .05), planning (P less than .05), and skipping (P less than .01). Similarly, patients with HIV infection were more adherent in terms of frequency of infusion than patients without infection.
The researchers also found significant correlations among all the psychosocial variables measured and adherence to prophylaxis. For instance, patients who had poorer quality of life related to managing their physical health, pain, and emotions showed poorer planning of their treatment. Patients who had difficulty remembering treatment had poorer quality of life related to pain and vitality, but they also had greater conviction of disease and hypochondriasis.
“Intervention programmes should be aimed more at changing barriers that patients and caregivers encounter when accepting diagnosis and how they can adapt their resources and skills to better take advantage of the progress made in treatments,” the researchers wrote.
The study was supported by a grant from Pfizer. The researchers reported having no financial disclosures.
SOURCE: Torres-Ortuño A et al. Vox Sang. 2018 May 24. doi: 10.1111/vox.12669.
FROM VOX SANGUINIS
Preop Cognitive Issues and Surgery Type Affect Postop Delirium
Postoperative delirium has a high prevalence among vascular surgery patients, increasing morbidity, mortality and length of stay (LOS),according to Rima G. Styra, MD, and her colleagues at the University of Toronto (Canada).
In Friday’s Scientific Session 5, Dr. Styra will present their prospective study, which found that there were preop risk factors for delirium that can be determined by a surgical team in order to identify high risk patients; their study also looked at the impacts of delirium on hospital costs.
She and her colleagues preoperatively assessed 173 elective vascular surgery patients for cognitive function using the Montreal Cognitive Assessment Scale (MoCA) and the Confusion Assessment Method (CAM) for postoperative delirium, which was verified by chart and clinical review.
Demographic information, medications and a history of substance abuse, psychiatric disorders, previous delirium and the surgical procedure were prospectively recorded. An accompanying retrospective chart review of an additional 434 (elective and emergency) vascular surgery patients provided supplemental cost information related to sitter use and prolonged hospitalization secondary to three factors: delirium alone, dementia alone, and delirium and dementia.
Prospective screening of 173 patients (73.4% men, mean age 69.9 years), identified that 119 (68.8%) had MoCA scores indicating cognitive impairment, with 7.5% having severe impairment (dementia). Patients who underwent amputation had significantly lower MoCA scores (15.9 out of 30) compared to open and endovascular aortic surgery patients (23.6 out of 30). The normal range for MoCA is 25-30.
The incidence of delirium was 12% in the elective cohort. Regression analysis identified significant predictors of delirium including type of surgery: lower limb amputation (OR 16.7), open aortic repair (OR 5.3), and cognitive variables: dementia (OR 5.6), and MoCA scores indicating moderate to severe impairment (OR 5.6), and previous delirium (OR 3.0).
Retrospective review of 434 patients identified differences between sitter needs for patients with delirium and dementia (mean = 13.6 days), delirium alone (3.9 days) or dementia alone (less than 1day [17.7 hours]). A total of 15 patients required more than 200 hours (8.3 days), accounting for 69.7% of sitter costs for the surgical unit. Patients with underlying dementia who developed delirium accounted for 48% of the total surgical unit sitter days.
“Postoperative delirium is predicted by type of vascular surgery, impaired cognition (MoCA), and previous delirium. Costs and morbidity related to delirium are greatest for those with impaired cognitive burden. Preoperative MoCA screening can identify those at highest risk, allowing for patient and family education regarding post-operative delirium risk, procedure modification and informed care,” Dr. Styra and her colleagues concluded.
Friday, June 22
3:30–5 p.m.
HCC, Ballroom A/B
SS26: The Impact of Pre-Operative Cognitive Impairment and Type of Vascular Surgery on Postoperative Delirium and Cost Implications
Postoperative delirium has a high prevalence among vascular surgery patients, increasing morbidity, mortality and length of stay (LOS),according to Rima G. Styra, MD, and her colleagues at the University of Toronto (Canada).
In Friday’s Scientific Session 5, Dr. Styra will present their prospective study, which found that there were preop risk factors for delirium that can be determined by a surgical team in order to identify high risk patients; their study also looked at the impacts of delirium on hospital costs.
She and her colleagues preoperatively assessed 173 elective vascular surgery patients for cognitive function using the Montreal Cognitive Assessment Scale (MoCA) and the Confusion Assessment Method (CAM) for postoperative delirium, which was verified by chart and clinical review.
Demographic information, medications and a history of substance abuse, psychiatric disorders, previous delirium and the surgical procedure were prospectively recorded. An accompanying retrospective chart review of an additional 434 (elective and emergency) vascular surgery patients provided supplemental cost information related to sitter use and prolonged hospitalization secondary to three factors: delirium alone, dementia alone, and delirium and dementia.
Prospective screening of 173 patients (73.4% men, mean age 69.9 years), identified that 119 (68.8%) had MoCA scores indicating cognitive impairment, with 7.5% having severe impairment (dementia). Patients who underwent amputation had significantly lower MoCA scores (15.9 out of 30) compared to open and endovascular aortic surgery patients (23.6 out of 30). The normal range for MoCA is 25-30.
The incidence of delirium was 12% in the elective cohort. Regression analysis identified significant predictors of delirium including type of surgery: lower limb amputation (OR 16.7), open aortic repair (OR 5.3), and cognitive variables: dementia (OR 5.6), and MoCA scores indicating moderate to severe impairment (OR 5.6), and previous delirium (OR 3.0).
Retrospective review of 434 patients identified differences between sitter needs for patients with delirium and dementia (mean = 13.6 days), delirium alone (3.9 days) or dementia alone (less than 1day [17.7 hours]). A total of 15 patients required more than 200 hours (8.3 days), accounting for 69.7% of sitter costs for the surgical unit. Patients with underlying dementia who developed delirium accounted for 48% of the total surgical unit sitter days.
“Postoperative delirium is predicted by type of vascular surgery, impaired cognition (MoCA), and previous delirium. Costs and morbidity related to delirium are greatest for those with impaired cognitive burden. Preoperative MoCA screening can identify those at highest risk, allowing for patient and family education regarding post-operative delirium risk, procedure modification and informed care,” Dr. Styra and her colleagues concluded.
Friday, June 22
3:30–5 p.m.
HCC, Ballroom A/B
SS26: The Impact of Pre-Operative Cognitive Impairment and Type of Vascular Surgery on Postoperative Delirium and Cost Implications
Postoperative delirium has a high prevalence among vascular surgery patients, increasing morbidity, mortality and length of stay (LOS),according to Rima G. Styra, MD, and her colleagues at the University of Toronto (Canada).
In Friday’s Scientific Session 5, Dr. Styra will present their prospective study, which found that there were preop risk factors for delirium that can be determined by a surgical team in order to identify high risk patients; their study also looked at the impacts of delirium on hospital costs.
She and her colleagues preoperatively assessed 173 elective vascular surgery patients for cognitive function using the Montreal Cognitive Assessment Scale (MoCA) and the Confusion Assessment Method (CAM) for postoperative delirium, which was verified by chart and clinical review.
Demographic information, medications and a history of substance abuse, psychiatric disorders, previous delirium and the surgical procedure were prospectively recorded. An accompanying retrospective chart review of an additional 434 (elective and emergency) vascular surgery patients provided supplemental cost information related to sitter use and prolonged hospitalization secondary to three factors: delirium alone, dementia alone, and delirium and dementia.
Prospective screening of 173 patients (73.4% men, mean age 69.9 years), identified that 119 (68.8%) had MoCA scores indicating cognitive impairment, with 7.5% having severe impairment (dementia). Patients who underwent amputation had significantly lower MoCA scores (15.9 out of 30) compared to open and endovascular aortic surgery patients (23.6 out of 30). The normal range for MoCA is 25-30.
The incidence of delirium was 12% in the elective cohort. Regression analysis identified significant predictors of delirium including type of surgery: lower limb amputation (OR 16.7), open aortic repair (OR 5.3), and cognitive variables: dementia (OR 5.6), and MoCA scores indicating moderate to severe impairment (OR 5.6), and previous delirium (OR 3.0).
Retrospective review of 434 patients identified differences between sitter needs for patients with delirium and dementia (mean = 13.6 days), delirium alone (3.9 days) or dementia alone (less than 1day [17.7 hours]). A total of 15 patients required more than 200 hours (8.3 days), accounting for 69.7% of sitter costs for the surgical unit. Patients with underlying dementia who developed delirium accounted for 48% of the total surgical unit sitter days.
“Postoperative delirium is predicted by type of vascular surgery, impaired cognition (MoCA), and previous delirium. Costs and morbidity related to delirium are greatest for those with impaired cognitive burden. Preoperative MoCA screening can identify those at highest risk, allowing for patient and family education regarding post-operative delirium risk, procedure modification and informed care,” Dr. Styra and her colleagues concluded.
Friday, June 22
3:30–5 p.m.
HCC, Ballroom A/B
SS26: The Impact of Pre-Operative Cognitive Impairment and Type of Vascular Surgery on Postoperative Delirium and Cost Implications
Transcarotid vs. Transfemoral Carotid Artery Stenting in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
The Safety and Efficacy Study for Reverse Flow Used during Carotid Artery Stenting Procedure (ROADSTER) multicenter trial reported the lowest stroke rate in high-risk patients compared with any prospective trial of TFCAS, according to Mahmoud B. Malas, MD, of the Johns Hopkins Hospital and his colleagues. However, clinical trials have selection criteria that exclude many patients, and are highly selective of operators performing the procedures, which limit generalizability. Dr. Malas will present a study in Scientific Session S4 that he and his colleagues did to compare in-hospital outcomes after TCAR and TFCAS as reported in VQI.
They analyzed data from the initial 646 patients enrolled in the SVS VQI TCAR Surveillance Project (TSP) and compared it with that of patients who underwent TFCAS between 2005 and 2017. Patients with tandem, traumatic, or dissection lesions were excluded. They used multivariable logistic regression and 1:1 coarsened exact matching (CEM) to analyze neurologic adverse events [stroke and transient ischemic attacks (TIAs)] and in-hospital mortality. Patients in the two procedures were matched on age, race, coronary artery disease, congestive heart failure, prior CABG/PCI, chronic kidney disease, diabetes, ASA class, symptomatic status, restenosis, anatomical and medical risk, emergency status, and preoperative medication use.
Compared with more than 10,000 patients undergoing TFCAS, the 638 undergoing TCAR were significantly older and had more cardiac comorbidities. In contrast, patients in the TFCAS group were more likely to be symptomatic and to have a restenotic lesion. There was no significant change in the odds of stroke/death in TFCAS over the study period.
The rates of in-hospital TIA/stroke as well as TIA/stroke/death were significantly higher in TFCAS compared with TCAR (3.3% vs.1.9% and 3.8% vs.2.2%, respectively; both P = .04). In both procedures, symptomatic patients had higher rates of TIA/stroke/death compared with asymptomatic patients; however, the difference was significant only in the TFCAS (5.3% vs. 2.7%, P less than .001). On multivariable analysis, TFCAS was associated with twice the odds of in-hospital neurologic events and TIA/stroke/death compared with TCAR, independent of symptomatic status. CEM showed similar results.
“Our results show that patients undergoing TCAR had significantly higher medical comorbidities, but half the risk of in-hospital TIA/stroke/death compared to patients undergoing TFCAS. This initial evaluation of VQI TSP demonstrates the ability to rapidly monitor new devices/procedures in real world practice. While preliminary, this is the first study to confirm the benefit of TCAR compared to TFCAS in real-world practice,” Dr. Malas concluded.
Friday, June 22
3:30 - 5 p.m.
HCC, Ballroom A/B
SS24: Transcarotid Artery Revascularization (TCAR) vs. Transfemoral Carotid Artery Stenting (TFCAS) in the SVS Vascular Quality Initiative
Herpesvirus infections may have a pathogenic link to Alzheimer’s disease
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
FROM NEURON
Mother Knows Best
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
About six months ago, an 8-year-old girl developed an asymptomatic rash near her ear. Her mother suspects it is psoriasis, which runs heavily in the family—but their primary care provider favors a fungal diagnosis. He prescribes a succession of topical and oral antifungal medications (including nystatin and terbinafine), which yield no discernable improvement. At this point, referral to dermatology is made.
The child’s mother denies any history of recent infections (eg, strep throat) on her daughter’s behalf. Furthermore, there are no reports of pain associated with the rash or elsewhere.
EXAMINATION
The rash, which is confined to the external right ear, is composed of uniformly smooth white scale on a faintly salmon base. The entire lesion measures about 3 cm at its widest point, and the margins are arciform and well-defined.
No such lesions are seen elsewhere, but tiny pits can be seen on one fingernail.
What is the diagnosis?
DISCUSSION
A punch biopsy could have confirmed the diagnosis, but with the family history, classic appearance, and lack of response to antifungal medication, there was little doubt that this was a case of psoriasis. This autoimmune disease affects nearly 3% of the white population in this country and has a genetic component about 30% of the time.
In psoriasis, keratinocytes matriculate upward from the basal layer to the skin surface at four times the normal rate—so quickly that they have no chance to lose their nuclei (as they normally would). They then pile up, creating plaques of micaceous white scale on a salmon-pink base. Histologically, the smoothly undulating dermoepidermal junction is jammed together, producing fused ridges with clumps of neutrophils on their tips.
While it favors extensor surfaces of extremities, psoriasis can show up anywhere on the body—on the genitals, mouth, and in the nails, where it can cause pits, dystrophy, discoloration, onycholysis, and onychorrhexis.
Unfortunately, this is probably just the beginning of this child’s psoriasis. The good news is that we’re in a golden age of psoriasis treatment, with more drugs than ever to choose from and even more in development. For this patient, we used a keratolytic agent (urea lotion) to thin out the surface scale, in order to allow a class 4 steroid cream to reach the pink inflammatory portion. Within a month, most of this patch had cleared, though we can be fairly sure it and others like it will be back. Education and ongoing follow-up will be needed, in case she is among the 20% to 25% of patients who will develop psoriatic arthropathy, a crippling form of arthritis.
It is certainly possible to develop a fungal infection on or in an ear, but for that to happen, there has to be a source (eg, animal, person, soil). Moreover, the scale would look entirely different, with clearing centers and advancing margins. The likely truth is that this was called “fungal” for lack of any other suspects.
TAKE-HOME LEARNING POINTS
- White scale on a salmon-pink base typifies psoriasis vulgaris, a very common diagnosis that is often mistaken for fungal infection; biopsy can be extremely helpful in establishing or ruling out this diagnosis.
- Psoriasis has a genetic basis, with many gene loci identified to date, but only about 30% of affected patients can attest to a family history.
- In addition to having unsightly, often itchy lesions, psoriasis patients are also at risk for psoriatic arthropathy, a potentially crippling condition.
- The best news is that we have many drugs with which to treat this disease, including a whole family of drugs termed “the biologics,” which directly (and successfully!) address the disease.
Don’t Miss Practice Management Tips for Novice and Seasoned Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Young vascular surgeons looking to make their marks and balance their lives, as well as more experienced surgeons seeking tips for more effective practice and career management, should consider the session led by Jeffrey Siracuse, MD, of Boston Medical Center, and Courtney Warner, MD, of Albany Medical College, Saratoga Springs, N.Y.
“This will be a great and informative session that, although geared toward young surgeons, will be highly useful for surgeons of all experience levels,” Dr. Siracuse said of the session.
“Topics include building a successful academic practice, building a successful private practice, how to work with other specialties, how to negotiate a contract, how to improve one’s current job, and more on the business side of medicine,” said Dr. Siracuse. The discussions will be followed by a Q&A panel.
The first job after a fellowship is often the first “real job” of any type that new surgeons have had, Dr. Siracuse said. Medical school offers many things, but young surgeons may be underprepared for how to negotiate for one’s first surgical position and how to set oneself up for success, he explained. That said, the keys for success are significantly different for surgeons entering an academic setting or private practice, he noted.
The session kicks off with presenters addressing both types of practice.
Faisal Aziz, MD, of Penn State Hershey College of Medicine, Hershey, addresses the “Top 10 Roadblocks to a Successful Academic Practice,” and Scott Berman, MD, of Carondelet Medical Group in Tucson, Ariz., takes on the “Top 10 Roadblocks to a Successful Private Practice.”
Some subjects likely to prompt lively discussion among seasoned veteran surgeons as well as novices include how to effectively negotiate and renegotiate contracts. The contracts presentation, “Top 10 Tips on Negotiating Contracts and Other Things I Learned in Business School,” is scheduled to be given by Bruce Perler, MD, of Johns Hopkins University in Baltimore, Md.
In addition, surgeons at all levels of experience can benefit from tips on how to work with individuals in other specialties, especially if one is competing with them for patients and cases, Dr. Siracuse said. Brandon Propper, MD, of San Antonio Military Medical Center, Texas, steps up to the plate with his “Top 10 Ways to Work With Other Specialties.”
The Practice Management Tips and Tricks for Young Vascular Surgeons session is recommended by the Community Practice Committee and the Young Surgeons Committee.
Friday, June 22
1:30 – 3:00 p.m.
HCC, Room 311
C5: Practice Management Tips and Tricks for Young Vascular Surgeons
Mix and Mingle at Friday’s Closing Reception
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Mark the closing of the Exhibit Hall by attending the Closing Reception, set for 4:30 to 5:30 p.m. Friday in the Auditorium on Level 2 of the Hynes Convention Center.
VAM attendees have one more chance to visit with vendors and check out innovations in devices and medications. Guests have another to meet with friends old and new, to relax, and to enjoy cocktails and hors d’oeuvres.
Tickets are required and are available at Registration.
Advanced Practice Providers Vital to Vascular Team
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
The team approach has changed the entire field of medicine in the past 10-20 years and, in fact, is critical to optimal patient outcomes. That’s according to Anil Hingorani, MD, who will co-moderate a special forum Friday, “Improving Clinical Metrics With the Utilization of Advanced Practice Providers.”
It will be held from 1:30 to 3 p.m. in Ballroom A/B.
The team approach is front and center at this year’s Vascular Annual Meeting, which carries the theme: “Home of the Vascular Team – Partners in Patient Care.”
“Our vascular disease patients can be quite complex,” said Dr. Hingorani. “We will highlight that to take care of these complexities we need a team approach, and our team members can help tremendously.” This is true across the setting spectrum, be it rural, urban, suburban.
“Some NPs and PAs run our service. They help coordinate pre-op evaluations, post-op management, take care of research protocols, billing, and other office responsibilities,” he said.
He pointed out he is not a specialist in diabetes, but that his NP has a special interest and passion for the topic. The work she does for their diabetic patients “helps MY patients and helps MY procedures have better outcomes.”
PAs and NPs also help run research projects and are instrumental in working with fellows rotating through. With their work in what Dr. Hingorani referred to as the “three pillars” – clinical work, teaching, and research – they are tremendously important to the vascular team.
Advanced care providers also help improve outcomes, he said, when pay for performance and quantitating outcomes is becoming a standard part of health care. Admissions, discharges, surgical site infections, diabetes, follow-up all are important for patient care, and tracking all the details is vital to outcomes. It will be addressed in the forum, Dr. Hingorani said.
“Medicine is a specialty that hasn’t really caught on to MACRA, MIPS, and what pay for performance really entails,” he said. “Many are still figuring out, ‘What changes do I need to make to make this work for my patients and me? Where does my practice fit in?’ We’re going to have to keep working on that.”
Speakers will be primarily nurse practitioners and physician assistants. “We didn’t want surgeons telling PAs and NPs what they should be doing. It needs to be the PAs and NPs doing the speaking, focusing on issues important to them.”
Dr. Hingorani believes that the Vascular Annual Meeting is the first to stress the team approach theme. “I think it’s an important step and others will follow suit,” he said. “These ideas are resonating. They’re important and will be the way forward.
“I think we’ll be breaking new ground and will ripple across the societies.”
Besides a panel discussion at the end, forum topics include:
- Improving Metrics in Clinical Practice: The Value of APPs to a Vascular Practice
- There’s an APP for That: Workforce and Community Practice Experience
- National and International Trends in the Use of APPs, PAs in Surgery and Outcome Data
- Improving Metrics via Team-Based Care: The Wake Forest Baptist Health Experience
- Influence of APPs - MIPS and “Throughput” of Patients, Value/Quality/Financial Benefit and APPs
- Funny You Should Ask: What Advanced Practice Providers Bring to the Table
- How Advanced Practice Clinicians Can Add Value to Your Practice
- Driving Outcomes: University of Maryland Advanced Practice Providers Target Preventable Complications, Length of Stay, and Readmissions Univers LT Std
Dialectical behavior therapy reduces suicide attempts in adolescents
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
A form of behavioral therapy that focuses on enhancing emotion regulation, distress tolerance, and improving quality of life has shown promise in reducing self-harm and suicide attempts in adolescents, according to new research.
In a paper published in JAMA Psychiatry, researchers reported the outcomes of a randomized trial of dialectical behavior therapy (DBT) versus individual and group supportive therapy in 173 adolescents with a history of suicide attempts.
DBT, developed by Marsha Linehan, PhD, as a team-based intervention for chronically suicidal patients with borderline personality disorder, is aimed at getting patients to focus on changing their behaviors so that they are able to meet their long-term goals. The use of DBT with adults has been tied to low dropout rates, and has been effective at reducing suicide attempts and self-harm.
In the study, the DBT consisted of weekly individual psychotherapy, multifamily group skills training, youth and parent telephone coaching, and a weekly therapist team consultation. The control group took part in individual sessions, group therapy, as-needed parent sessions, and a weekly therapist team consultation.
Researchers saw a 70% lower rate of suicide attempts, 68% lower rate of nonsuicidal self-injury, and 67% lower rate of self-harm in the DBT group, compared with the control group at the end of the 6-month treatment course. However, at 12 months, the differences between the two groups were no longer statistically significant.
“This is the first adolescent RCT [randomized, controlled trial] to our knowledge to demonstrate that DBT is effective at decreasing suicide attempts,” Elizabeth A. McCauley, PhD, of the Seattle Children’s Research Institute, and her coauthors.
At 12 months, those figures were 51.2% and 32.2% respectively.
Significantly, more participants in the DBT group completed the treatment, compared with those in individual and group supportive therapy (75.6% vs. 55.2%), although this did not appear to be responsible for the difference in outcomes.
“Although results of pattern-mixture models found no evidence of an informative attrition mechanism, we cannot rule out the possibility that differential treatment exposure is a mechanism that leads to the DBT outcomes,” the authors wrote. “Stronger DBT treatment retention is, however, an important finding given prior research that found difficulties with treatment engagement, and adherence among suicidal and self-harming youths.”
Parents were involved in both treatments, but “DBT included greater family involvement,” Dr. McCauley and her coauthors wrote. “This difference may have contributed to both greater retention and treatment effects, particularly because stronger family components are associated with treatment benefits for adolescent self-harm.”
The authors said the fact that both groups improved after 12 months provided support for the individual and group supportive therapy in these patients.
“Our findings add to data supporting other promising treatment approaches, including cognitive-behavioral therapy, mentalization-based therapy, and family-based treatments,” they concluded
The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
SOURCE: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi:10.1001/jamapsychiatry.2018.1109.
FROM JAMA PSYCHIATRY
Key clinical point: Dialectical behavior therapy reduces suicide attempts and self-harm in adolescents.
Major finding: DBT showed a 70% reduction in suicide attempts, compared with controls.
Study details: A randomized, controlled study of 173 adolescents with a history of suicide attempts.
Disclosures: The study was supported by the National Institutes of Mental Health. Eight authors declared grant support from NIMH, and two authors declared other funding unrelated to the study.
Source: McCauley EA et al. JAMA Psychiatry. 2018 Jun 20. doi: 10.1001/jamapsychiatry.2018.1109.